The present invention is related to an apparatus and a method to carry out radiotherapeutic or radiosurgical treatments using kilovoltage X-ray beams, that is, those whose energy spectrum lies within the range varying between 20 keV to 500 keV. The term image guided radiotherapy is used in reference to the combination of an image acquisition system and a radiation generating ionizing equipment (X-rays, electrons, protons, neutrons and others) used to deliver radiation doses to any structure which can be, but is not limited to, a tumor or an arterio-venous malformation (AVM). The system for image acquisition, through the obtaining of a series of radiologic images, is in charge of “guiding” the way in which the ionizing radiation beam is directed towards the object to be treated in such a way that the beams are aimed towards the tumor or AVM, attempting to minimize the radiation to the healthy tissues and structures which surround it. The image acquisition system can consist of a computerized axial tomography (CAT), a nuclear magnetic resonance imaging (NMRI), cone beam computerized tomography system (CBCT), or stereo graphic projections obtained through a conventional digital radiographic system.
The technology available for the treatment of tumors or AVMs using ionizing radiations has evolved beginning from the kilovoltage X-ray machines, the cesium or cobalt sources (with energies of 0.66 MeV and 1.25 MeV respectively), up to the modern computer-controlled linear accelerators capable of producing radiation beams with peak energies of up to 25 MeV for X-rays and of up to 20 MeV for electrons. The purpose of trying to reach high energies for the treatment of non-surface tumors in radiotherapy is tied to the physics of the interactions between the radiation and matter: the beam with the highest energy has not only greater penetration power (greater absorbed dose at depth as compared to lower energy beams), but also the absorbed dose at points close to the surface of the objects being irradiated is lesser in correlation to the increase of the beam's energy. For example, when an X-ray beam with maximum spectral energy of 15 MeV is compared to an X-ray beam with maximum spectral energy of 150 keV, the radiation doses at a depth of 10 cm, typical for example in prostate tumors, is 80% of the maximum for the 15 MeV beam and only 35% of the maximum for the 150 keV beam. It is worth mentioning, however, that as the energy of the radiation beam being used increases, so does the economic cost not only of the apparatus which generates radiation, but also of the installations necessary to accommodate it, given the amount of shielding required to confine the radiation emitted to the treatment room. The kilovoltage x-ray beams, on the other hand, can be produced at a fraction of the cost of the megavoltage x-ray beams, the installations necessary to accommodate them require much less shielding and the generating equipment is compact and requires simple maintenance. However, given the low penetration of this type of radiation, its use has been limited to the treatment of surface tumors, that is, those found at no greater depth than 2 cm in the patient. For tumors found at a greater depth, using kilovoltage X-rays exposes the healthy tissues which are found in the beam's trajectory before reaching the tumor, to excess radiation.
The problem is the following: given the low penetration of the X-ray beams with energies in the 20 KeV-500 KeV range, very little radiation reaches the tumor, and that which does reach it, is inefficiently absorbed given the uncertain nature of the interaction of the radiation with the matter. At the beginning of the 1980's, Mello and collaborators reported that the use of iodinated agents (solutions with an iodine base) incorporated into experimental tumors, those implanted into animals for laboratory study, would show better response when they were radiated with kilovoltage X-rays as compared to tumors lacking the incorporation of the iodinated agents (Mello R S et. al. Phys. Med. Biol. Vol 10 pp 75-78, 1983). The iodine or gadolinium based compounds absorb the X-rays in a preferred manner in this energy range, given mainly to the photoelectric effect and thus are routinely used in diagnostic radiology to highlight organ visibility. This application in particular gives rise to the term “contrast agent”.
It is important to highlight that this effect only occurs for the combination of the contrast agent and kilovoltage X-rays with energies ranging between 40 keV to 150 keV, given that at these energies, the main interaction mechanism between the X-rays and the matter is through the photoelectric effect, which is not the case for the beams with energies in the megavoltage range, as they interact mainly through other mechanisms (Compton effect and pair production). This increase in the X-ray absorption caused by the incorporation of the contrast agent into the tumor is responsible for the better response of the tumor to the radiation observed by Mello and collaborators. In 1994, the first attempt to clinically apply this treatment embodiment was reported: Rose and collaborators used a Computerized Tomography Scanner, with an X-ray spectrum with energy spikes in an order of 150 keV, to carry out treatments of cerebral tumors using an iodine based contrast agent (Rose J H et. Al. Int. J. Radiat. Oncol. Biol. Phys. Vol. 30 pp. 24-25, 1994). The treatment was administered in conjunction with conventional radiotherapy using megavoltage beams, and cerebral tumors were chosen given that the depths at which such tumors are found generally do not exceed 5 cm. Only a small fraction of the total dose was administered with the axial tomography scanner. The concentration of the contrast agent reported in the tumor was that of 10 mg of iodine per gram of tissue (10 mg-l/g), however, this is merely an estimate by the scientists who carried out the study and not a quantitative measurement.
Recently, it has been reported that experimental contrast agents based on gold nanoparticles dissolved in a saline solution produce a similar effect to that reported by Mello and collaborators, with the advantage that in principle, metallic nanoparticles with a diameter in the 2 nm range, accumulate preferentially in the tumor (Hainfeld J F et. al. Phys. Med. Biol. Vol. 49 pp N309-N315), 2004). Recently it has been shown that using rotational irradiation techniques, it is possible to irradiate tumors at depths of 10-12 cm using the clinically available iodine or gadolinium based contrast agents (Garnica-Garza H M Technol. Cancer Res. Treat. Vol. 9 pp 271-278, 2010) as well as experimental contrast agents such as could be those based on metallic nanoparticles, particularly gold and bismuth (Garnica-Garza H M Phys. Med. Biol. Vol. 54 pp 5411-5425, 2009).
It has also been shown that even though the treatments can be acceptable with regards to the radiation doses received by the tumor, certain bone structures receive doses which are too high. Additionally, given that the bone structures which surround the tumor attenuate in a very pronounced way the X-rays which are directed unto the tumor, the resulting doses which are absorbed by the tumor are very non-uniform. It has also been shown that the radiation beams must be filtered in a significant manner to remove the very low energy X-rays, as these low energy X-rays interact at a very short distance from the surface, increasing the dosage absorbed by the skin which represents a serious limitation to the clinical application of this treatment embodiment. The need to filter the used X-ray beams presents a problem to the possible clinical application of this treatment technique, seeing that upon filtering an X-ray beam in a significant manner, the amount of radiation which reaches the tumor is also reduced, resulting in longer treatment times, which represents a serious disadvantage. Another of the problems with the clinical application of this new treatment embodiment arises from the fact that the absorbed doses imparted to a point within the subject to be irradiated depends on the local concentration of the contrast agent at that specific point, and not quantifying such a concentration in an appropriate manner at each point within the tumor or malformation to be irradiated results in the significant degradation in the quality of the treatment (Garnica-Garza H M Phys. Med. Biol. Vol. 54 pp 5411-5425, 2009).
In the state of the art there exist several applications and patents which refer to equipment and methods for delivering radiotherapy, some of which are described as follows:
Application number; 9807896. Title: Therapy and Surgical Treatment System by means of Radiation and Methods of use of the same. The summary which is published for this invention provides the following: A radio surgical and radiotherapy system to provide a diagnostic and locating image of the object through tridimensional mapping of the patient in third dimension by such means as the CT Scanner or MRI, placement of the patient on an examining table with a four degree freedom of movement, and a stereotactic therapy unit with cobalt 60 is provided which incorporates multiple sources to irradiate an object; methods of radiosurgery and radiotherapy which use the system are also provided; a configuration of the combination of the radiation source, 360° rotation characteristics of the therapy unit and the movement of the table will allow irradiating any size and shape of the object at therapeutic levels while the radiation exposure to surrounding healthy tissue is minimized; also a stopper of radiation beams is provided, which captures more than 80 percent and preferably more than 90% of the radiation of the sources of radiation.
Application number: PA/a/2006/003787. Title: Planning System, Method and Apparatus for Radiation Therapy. The published summary of this invention provides the following: A system and the associated methods to determine optimal radiation beam arrangement are described. The system includes a computer based planning apparatus which optimizes the treatment plan, which has a memory and an entrance device which is in communication with the computer to optimize the treatment plan to provide access to the operator to control the software functions in order to optimize the plan. A device which obtains images is in communication with the optimizing computer for the treatment plan, through a communications network, in order to provide a part of the image of the objective tumor's volume and the volume of the structure which is not the objective. The software for the optimizing plan is obtained computationally and later optimizes a proposed radiation beam arrangement, repeating based on the constrictions, to form an optimized arrangement of the radiation beam. An administering therapeutic device with radiation, according, in communication with the computer optimizing the treatment plan, through the communication network, later applies the optimized radiation beam arrangement to the patient.
Application number: WO 2007/133932. Title: Deforming Register for Radiotherapy Images directed by Images. The published summary of this invention provides the following: A system and method to develop radiotherapy plans and a system and method to develop a radiotherapy plan to be used in radiotherapy treatments are disclosed. A radiotherapy plan is developed using a register of medical images. The register is based on the identification of the signals found within the internal structures of the body.
U.S. Pat. No. 7,603,164 B2. Title: Compound System for Radiotherapy. The published summary of this invention provides the following: A compound system for radiotherapy includes a CT scanner to prove the position of the affected portion to be irradiated in a patient, an apparatus for irradiating is available, based on the positional information of the affected portion verified by the CT scanner, of the patient in a specific position in which the affected portion is aligned in an irradiating position, and the carrying out of the irradiation to the affected portion, a common bed used for the CT scanner and the irradiation apparatus, in a state where the patient is in prone position on the common bed and means of movement to move the patient from the CT scanner to a specific position within the irradiation apparatus. The means of movement move the patient on the common bed to a specific position by causing either linear movement of the CT scanner and the irradiation apparatus, linear movement of the CT scanner and curving movement of the irradiation apparatus, curving movement of the scanner and the irradiation apparatus and linear movement of the CT scanner, linear movement of the CT scanner and the common bed, and linear movement of the CT scanner and curving movement of the common bed. With this compound system, at the time of radiotherapy to the tumor or similar, the affected portion can be irradiated in a state in which the position of the affected portion aligned by a CT scanner is maintained with precision. As a result, it is possible to significantly increase the control with exactitude of the position of the affected portion in radiotherapy and as such significantly increase the effect of radiotherapy.
U.S. Pat. No. 5,207,223. Title: Apparatus and Method for the Development of Stereotactic Surgery. The published summary of this invention provides the following: A method and apparatus are available to selectively irradiate a blank within a patient. A three dimensional sketch of a region surrounding the target is provided. A radiation emitting apparatus emits a collimated beam. Diagnostic beams at a known angle other than zero from each other travel through the sketched region. These diagnostic beams produce projection images within the sketched region. Electronic representations of the images are compared to the reference data, in such a way that the target is located. The relative positions of the emitting apparatus and the live organism are adjusted in such a way that the collimated beam is focused unto the target region. The comparison is repeated at small time intervals and when the comparison thus indicates, the adjustment step is repeated as needed, and in such a way that the collimated beam remains focused on the blank region.
The patents and applications, whose summaries are described above, do not precede the invention of the present application and therefore shall be described as follows.
In U.S. Pat. No. 7,603,164 B2, a linear accelerator (apparatus which produces X-rays with peak energies from 4 MeV up to 20 MeV) is coupled to a computerized tomography scanner (CAT), to snap images of the patient's internal geometry in order to determine where to aim the linear accelerator to. So this is indeed radiotherapy system which is guided by images. A significant problem with this patent is that the use of the CAT scanner and the accelerator cannot be simultaneous given the large volume of both apparatuses, it is impossible to take the image during the irradiation of the patient, so first the image is taken, the scanner is moved away from the patient, and the accelerator is placed then proceeding to irradiate the tumor. In the present invention to be described, given that the X-ray equipment with energy in the kilovoltage range (necessary to be used in conjunction with a contrast agent) is compact (weight ˜50 kg compared to the 2 to 3 tons of a linear accelerator) and given the design which is used, the taking of radiological images can be done in real time during the irradiation of the tumor, which is a great advantage, as it has been proven that tumors move during the irradiation of the same (due to, for example, the patient's breathing movements, the beatings of the heart etc.) in such a way that the tumor's movement can be followed in real time and the necessary corrections be made, also in real time to aim the X-ray beams unto the tumor's actual position and not where it was 3 or 4 minutes prior. The use of a plurality of X-ray sources to irradiate the tumor is also a significant difference, given that in U.S. Pat. No. 7,603,164 only one linear accelerator is used (that is, one source) to irradiate the tumor.
In U.S. Pat. No. 5,207,223, one linear accelerator and two diagnostic X-ray tubes are used, placed at a certain angle from each other to determine the position of the tumor or malformation during treatment and to thus carry out image guided radiotherapy procedures. A problem with this apparatus is that the diagnostic X-ray equipment used only provides bi-dimensional images of the site to be irradiated, so that even though it is possible to determine lateral tumor movements with respect to the image plane of the tumor, it is impossible to determine movements in the direction of the X-ray beam's incidence. So the tumor movement can only be tracked in two dimensions. Another limiting factor of this apparatus is that it only uses one collimated radiation source to produce circular beams with variable diameter, not taking into account the possibility of producing fields in other geometric forms. In the present invention a plurality of treatment sources are used capable of producing fields with varied geometric forms in addition to being capable of monitoring the tumor or malformation's position in three dimensions in real time.
In patent application WO 2007/133932, a method is described to effect radiotherapy planning using radiologic images taken before and during radiation treatment. The method uses internal markers, which can be bone structures in the patient or tiny gold spheres surgically inserted into the tumor, to determine how organs and tissues are deformed in a patient during the radiation application due to the physiologic movements of said patient. The method described in said application employs a series of computerized tomography images, taken at different time instances, and uses them to carry out a radiotherapy plan. A problem with this method is that it assumes the same pattern of deformity of the patient's inner structures occurs both at the time at which the images were taken as at the time of the patient's radiation treatment, which is not necessarily the case, given that physiologic movements are variable. Additionally, no technique is described to monitor the movement and deformation of the inner structures in real time during treatment.
In patent application number 9807896, a radiotherapy and radiosurgical apparatus is described which uses a plurality of sources in conjunction with a computerized tomography scanner or nuclear magnetic resonance scanner to identify the site to be irradiated. The computerized tomography scanner (CAT) or nuclear magnetic resonance (NMR) is found placed in separate and opposite sites to the radiation sources. The system includes a support table for the patient which can rotate up to 180° which is placed between the tomography scanner or nuclear resonance and the apparatus which contains the radiation sources, in such a way that through the rotation of the patient's support table it is possible to place said patient in the scanner to identify the geometry of the site to be irradiated and afterwards, by means of an opposite rotation of the support table, place it in the position in which it will be irradiated. A problem with this is that it is not possible to use the CAT scanner or NMR in a simultaneous manner with the application of radiation on the tumor or malformation, that is, first the images of the geometry of the site to be treated with the CAT scanner or NMR are obtained, and afterwards the radiation can be applied. As was previously mentioned, this is not the most convenient given that the tumor or malformation can move during the application of radiation. Another problem with the described invention is that the plurality of radiation sources point unto a same focal point, and additionally, are contained in a single mechanism, that is, they lack independent movement from one another so that they all must be pointed to the same point and with the same orientation. As shall be described in detail later, the apparatus and method described in the present invention differ considerably from the patent application just described, seeing that, firstly, with the apparatus object of the present invention it is possible to accomplish the monitoring in real time of the position of the tumor or malformation during the application of radiation. Additionally, the plurality of sources which form part of the present invention are capable of irradiating the tumor or malformation from a plurality of positions not necessarily contained on a plane in addition to also irradiating more than one region of the tumor or malformation simultaneously, which is not the case in the patent application previously described and which grants flexibility at the time of irradiating the tumor or malformation, which is lacking in the apparatus of the described patent application.
Patent application number PA/a/2006/003787 presents an associated computing method and system to effect the planning of radiotherapy treatments using optimization algorithms. A planning of radiotherapy treatments basically consists of simulating in the computer the effects which different pertinent parameters on the radiation field used (radiation beam energy, collimation type, angle of incidence of the radiation beam on the patient, among others) have on the absorbed dose distributions which result in the volume of the patient to be treated. A problem with the invention presented in said patent application is that the system is designed to produce plans for high energy radiation treatments emanating from a linear accelerator or cobalt unit 60, which interacts with matter in a different way than the beams of low energy radiation, particularly in the way in which they are absorbed by high density structures, as can be, for example, bone structures. In this sense, the optimization of a radio therapeutic plan intended for a high energy radiation beam is not usable for a low energy beam.
From the above, it is gathered that to clinically implement a treatment technique for tumors and malformations using kilovoltage beams in conjunction with contrast agents, it is necessary to have a method and apparatus which together provide a complete radiotherapy and/or radiosurgical system capable of overcoming all and each of the limitations and problems previously described. In summary, to overcome all of these problems, one clinical implementation of this treatment embodiment requires a radiotherapy and/or radio surgical system with the following characteristics:                1. The system must allow the obtaining of three-dimensional anatomical images during the application of radiation to the patient, with the end purpose of monitoring not only the position of the tumor or malformation but also that of the bone structures which could surround it. Radiotherapy systems already exist which gather images of the patient with the end purpose of monitoring the position of the tumor, however, they only do so immediately before or after the application of the radiation and not during the application of said radiation.        2. The system must allow for spatial quantification of the presence of the contrast agent in the subject to be irradiated. By spatial quantification it must be understood that the system provides the three-dimensional distribution of the contrast agent within the patient. This quantification of the contrast agent must be carried out in real time during the application of radiation to the patient.        3. Based on the distribution of the contrast agent within the subject to be irradiated, the system must be capable of determining the combination of radiation beams whose application to the irradiated subject will result in a distribution of absorbed doses which accomplishes the treatment criteria specified by the radiation-oncologist physician.        4. The system must be capable of producing X-ray beams with a plurality of energy spectra in such a way that it provides a wide flexibility for the selection of the appropriate beam energy.        5. The system must be capable of producing reasonable treatment times, that is, in the 2 or 3 minute range.        6. To maximally reduce the dosages to the surface and be capable of reducing the attenuation of the radiation beam due to the bone structures, the system must have the necessary flexibility to allow the radiation beams to be aimed at the tumor from a plurality of sites not necessarily contained on a single plane surrounding the subject to be irradiated.        
Thus it is an objective of the present invention, to provide a system for the obtaining of three-dimensional anatomic images during the application of radiation to a patient with the end purpose of monitoring not only the position of the tumor or malformation, but also that of the bone structures which could surround said tumor.
Another objective of the present invention is to provide a system to spatially quantify the presence of a contrast agent in the subject to be irradiated, providing a three-dimensional distribution of the contrast agent within the patient.
Yet another objective of the present invention is that of providing a system which, based on the distribution of the contrast agent within the subject to be irradiated, determines the combination of radiation beams whose application to the irradiated subject results in a distribution of absorbed dose which satisfies the treatment criteria set by the radio-oncologist physician.
Another objective of the present invention is that of supplying a system which produces X-ray beams with a plurality of energy spectra in such a way that it provides a greater flexibility at the time of selecting the radiation beams.
Yet an additional objective of the present invention is that of providing a system which produces reasonable treatment times, that is, in the 2 to 3 minute range.
A further objective of the present invention is that of providing a system which reduces to the furthest extent possible the maximum absorbed dose imparted to the surface of the patient and is capable of reducing the attenuation of the radiation beam produced by the bone structures.
Lastly, another objective of the present invention is that of providing a system which possesses the necessary flexibility to allow the radiation beams be pointed to the tumor from a plurality of sites not necessarily contained on a single plane surrounding the subject to be irradiated.
Following are details of the method and apparatus of the present invention to carry out radiotherapy and/or radiosurgery with kilovoltage X-ray beams, in the presence of contrast agents incorporated into the subject to be irradiated, which in combination allow for the resolution of all and each of the problems associated with this treatment previously described.